In recent years, cancer has become the second leading cause of death after cardiovascular disease[1]. The treatments used for cancer mainly include surgery, radiotherapy and chemotherapy, and chemotherapy has become an important and essential strategy for cancer therapy by effecting different stages of tumor cell proliferation. However, several chemotherapeutic drugs are neurotoxic and can lead to chemotherapy-induced peripheral neuropathy (CIPN), a nerve disorder that can cause weakness, numbness, tingling and pain. CIPN is a major dose-limiting adverse effect of many anticancer drugs such as platinum salts (cisplatin, carboplatin and oxaliplatin), spindle poisons (taxanes and vinca alkaloids), bortezomib and thalidomide, and a potential reason to terminate or suspend chemotherapy, in some cases leading to disease progression[2-5]. For patients with CIPN symptoms, dose reduction or cessation of chemotherapy is not an effective solution, contrarily, it will make it difficult to manage cancer treatment, but not necessarily eliminate the neurotoxicity.
Up to date, the pathogenesis of CIPN has not been fully elucidated. It has been reported that the mechanism of peripheral neuropathy induced by taxol may be related to that axonal microtubule-associated protein makes axonal transport impaired[6]. Oxaliplatin-induced peripheral neuropathy may be caused by the chelation of calcium which can interfere with sodium ions-gated channels. According to the clinical research carried out by the National Cancer Institute and the World Health Organization, 15% of cancer patients treated with oxaliplatin suffered neurotoxicity at a cumulative dose of 780 to 850 mg/m2, while the risk increased to 50% at cumulative dose of 1170 mg/m2[7]. The body of the experimental evidence suggests that dorsal root ganglion (DRG) neurons are the main target of platinum drug-induced CIPN[8, 9]. Oxaliplatin acts on the DRG, leading to the damage of the cell bodies[10, 11], alterations in nuclearus morphology[12], selective atrophy of subpopulation of neurons[13], and degeneration of peripheral nerve axons[14]. The severity of damage and degeneration of DRG depend on doses and schedule of oxaliplatin administration. Pathologic changes in peripheral nerves are slighter than that of DRG. The phenomenon of axonal degeneration can only be seen for a few times, and the structure of myelin is basically normal. It has been reported that oxaliplatin can significantly reduce the volume of nucleolus of DRG neuron in mouse, and slow down the nerve conduction velocity[15]. The mechanism underlying oxaliplatin-induced chronic neurotoxicity is that oxaliplatin inhibits the synthesis of rRNA and protein in the nucleolus of neuronal cell bodies, resulting in morphological change and damage of sensory neurons[16].
Since CIPN seriously affects the efficacy of chemotherapy, the researchers throughout the world are actively looking for effective drugs and methods for treating and preventing oxaliplatin-indued peripheral neurotoxicity. Based on the mechanism of oxaliplatin-induced neurotoxicity, a series of methods have been proposed for CIPN control, but the results are unsatisfactory. Carbamazepine, a Na+ channel blocker, has been used in clinical studies for preventing the neurotoxicity of oxaliplatin. However, its preventive activity is shadowed in doubt because of its significant individual differences in plasma concentrations and adverse reactions including dizziness, somnolence, ataxia and others[17]. Amifostine, a preventive protector for the nephrotoxicity of cisplatin, is effective for treating oxaliplatin-induced peripheral neuropathy, but its cost is higher than the cost of chemotherapy per se. Clinical studies also indicated that gabapentin, calcium/magnesium salts, GSH, N-acetylcysteine and other drugs are effective for oxaliplatin-induced neurotoxicity, but their efficacy needs to be confirmed in the large-scale, randomized, and double-controlled experiments[18-20].
Oxaliplatin-induced neuropathy has a great impact on the quality of life of cancer patients. There are no curative conventional treatments, so further options have to be investigated. Traditional Chinese medicine (TCM) is a system of healing that is thousands of years old. It has long been proven successful treatment for chronic diseases and has also played an important role in the provision of health care in China. Based on clinical manifestation, CIPN belongs to the category of “arthralgia” in Chinese medicine. Its etiology and pathogenesis can be viewed in traditional Chinese medicine as qi and blood stagnation, damp accumulation, or kidney yin/yang deficiency. According to the principle in traditional Chinese medicine, i.e. the diagnosis and treatment should be made based on an overall analysis of the illness and the patient's condition, reinforcing Qi and nourishing Yin, as well as promoting blood circulation and removing obstruction in vessels, are major treatment methods for CIPN. Hence, taking the advantages of traditional Chinese medicine fully, there is a great potential to develop medicines that are effective, safe and cheap for preventing and treating CIPN from natural medicine resource, providing an adjuvant or alternative treatment to conventional treatment.